REVIEW

Physical activity, obesity and sedentary behavior in cancer

etiology: epidemiologic evidence and biologic mechanisms
Christine M. Friedenreich1,2,3 , Charlotte Ryder-Burbidge1 and Jessica McNeil1
1 Department of Cancer Epidemiology and Prevention Research, CancerControl Alberta, Alberta Health Services, Calgary, AB, Canada
2 Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
3 Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

Keywords An estimated 30–40% of cancers can be prevented through changes in

chronic inflammation; hormone; metabolism;
obesity; physical activity; sedentary behavior
Correspondence
C. M. Friedenreich, Department of Cancer
Epidemiology and Prevention Research,
CancerControl Alberta, Alberta Health
Services, Holy Cross Center, 2210-2nd St
SW, Calgary, AB T2S 3C3, Canada
E-mail: christine.friedenreich@
albertahealthservices.ca
(Received 15 June 2020, revised 8 July
2020, accepted 27 July 2020, available
online 18 August 2020)
doi:10.1002/1878-0261.12772
modifiable lifestyle and environmental risk factors known to be associated
with cancer incidence. Despite this knowledge, there remains limited aware-
ness that these associations exist. The purpose of this review article was to
summarize the epidemiologic evidence concerning the contribution of phys-
ical activity, sedentary behavior, and obesity to cancer etiology and to pro-
vide an overview of the biologic mechanisms that may be operative
between these factors and cancer incidence. Strong and consistent evidence
exists that higher levels of physical activity reduce the risk of six different
cancer sites (bladder, breast, colon, endometrial, esophageal adenocarci-
noma, gastric cardia), whereas moderate evidence inversely associates phys-
ical activity with lung, ovarian, pancreatic and renal cancer, and limited
evidence inversely correlates physical activity with prostate cancer. Seden-
tary behavior, independent of physical activity, has been shown to increase
the risk of colon, endometrial, and lung cancers. Obesity is an established
risk factor for 13 different cancer sites (endometrial, postmenopausal
breast, colorectal, esophageal, renal/kidneys, meningioma, pancreatic, gas-
tric cardia, liver, multiple myeloma, ovarian, gallbladder, and thyroid). The
main biologic mechanisms whereby physical activity, sedentary behavior,
and obesity are related to cancer incidence include an effect on endogenous
sex steroids and metabolic hormones, insulin sensitivity, and chronic
inflammation. Several emerging pathways related to oxidative stress, DNA
methylation, telomere length, immune function, and gut microbiome are
presented. Key recommendations for future research in both the epidemiol-
ogy and biology of the associations between physical activity, sedentary
behavior, obesity, and cancer risk are also provided.

obesity in cancer incidence has been evolving rapidly

1. Introduction
over the past three decades, and there is now convincing
The epidemiologic evidence base regarding the etiologic evidence for these associations. Research has also been
role for physical activity, sedentary behavior, and conducted to examine the underlying biologic

Abbreviations
BETA, Breast cancer and Exercise Trial in Alberta; BMI, body mass index; CRP, C-reactive protein; IGF, insulin growth factor; IGFBP, insulin
growth factor-binding protein; IL-1b, interleukin-1 b; IL-6, interleukin-6; MET, metabolic equivalents of task; PAGA, Physical Activity
Guidelines for Americans; RCT, randomized controlled trial; ROS, reactive oxygen species; RR, relative risk; SAA, serum amyloid A; SHBG,
sex hormone-binding globulin; TNF-a, tumor necrosis factor-a; UV, ultraviolet; WCRF/AICR, World Cancer Research Fund/American Institute
for Cancer Research.

790 Molecular Oncology 15 (2021) 790–800 ª 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use,
distribution and reproduction in any medium, provided the original work is properly cited.

C. M. Friedenreich et al.
mechanisms that could explain how these risk factors
are associated with increased cancer risk. Estimates of
the population burden associated with modifiable risk
factors and cancer incidence have demonstrated that
30–40% of cancers are potentially preventable [1–4] and
that some of the major risk factors associated with can-
cer include physical inactivity, sedentary behavior, and
obesity. Furthermore, there is a considerable economic
cost that could be avoided by decreasing the prevalence
of these modifiable risk factors [5]. At present, the glo-
bal prevalence of inactivity as defined by low levels of
physical activity, sedentary behavior, and obesity is high
[6,7]. Given that these risk factors are modifiable, there
is considerable potential to reduce the global burden of
cancer through interventions targeting these factors.
The aim of this paper was to provide an overview of the
current epidemiologic evidence associating physical
activity, sedentary behavior, and obesity with cancer
incidence, and the hypothesized biologic mechanisms
that are likely to connect these factors with cancer risk.
The paper concludes with recommendations for future
epidemiologic research on these topics to address some
of the remaining knowledge gaps.
2. Physical activity and cancer
incidence
Physical activity, defined as any bodily movement pro-
duced by skeletal muscles that requires energy expendi-
ture, has been characterized and investigated in
epidemiologic studies by the domain in which the activ-
ity is achieved (e.g., occupational, recreational, house-
hold, and transport activity), the volume of the activity
(as measured by the frequency, duration, and inten-
sity), and the time periods when the activity was done
(ranging from current to lifetime activity). To date,
over 500 observational epidemiologic studies have
examined some aspect of the association between phys-
ical activity and cancer incidence. Most recently, this
evidence has been evaluated and summarized for the
Physical Activity Guidelines for Americans (PAGA)
2018 Report as well as by the World Cancer Research
Fund/American Institute for Cancer Research
(WCRF/AICR) as part of their recommendations on
physical activity for cancer risk reduction [8,9]. These
reviews of the evidence, as well as multiple systematic
reviews and meta-analyses on this topic, have con-
cluded that there is some evidence for a reduced risk
of 11 different cancer sites when comparing the highest
to the lowest levels of physical activity (Table 1).
Specifically, there is strong evidence that physical
activity reduces the risk of bladder, breast, colon,
endometrial, esophageal adenocarcinoma, and gastric
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Physical inactivity and obesity in cancer etiology
cancers. There is moderate evidence for an association
between higher levels of physical activity with lower
occurrence of renal, ovarian, pancreatic, and lung can-
cers. Nevertheless, confounding by tobacco smoking
may exist for lung cancer. Limited evidence exists for
an association between increased physical activity and
decreased risk of prostate cancer. There is limited evi-
dence for an increased risk of melanoma with higher
physical activity levels. However, uncontrolled con-
founding by ultraviolet (UV) exposure in these studies
may explain this possible increased risk. The evidence
for an association between physical activity and other
cancer sites remains insufficient.
The magnitude of the decreased risk associated with
higher levels of physical activity ranges from about
10–25% for most of these cancer sites [10]. A dose–re-
sponse association between increasing levels of physi-
cal activity and specific cancer risk is evident for
several cancer sites but the methods for measuring and
categorizing physical activity levels across epidemio-
logic studies have been inconsistent which precludes
any definitive conclusions regarding the exact volume
of physical activity that provide given levels of effect.
Furthermore, insufficient evidence is available to deter-
mine if the association between physical activity and
cancer risk varies by domain or type (i.e., aerobic ver-
sus resistance exercise) of physical activity [8].
Limited information exists at present on how the
association between physical activity and cancer varies
by cancer subtypes. With respect to how physical
activity varies across population subgroups, there is
evidence that being physically active is equally benefi-
cial for men and women. Moreover, some evidence
suggests that lifelong activity is particularly beneficial.
However, activity later in life can also reduce cancer
risk (e.g., activity done after menopause has been
shown to reduce breast cancer risk irrespective of pre-
menopausal activity) [8]. There is also evidence that
physical activity benefits are comparable across all
racial and ethnic groups.
3. Sedentary behavior and cancer
incidence
Sedentary behaviors include all waking activities with
an energy expenditure ≤ 1.5 metabolic equivalents of
task (METs) performed in the sitting, reclining, or
lying postures (e.g., watching television, working at a
computer, sitting in a vehicle) [11]. It is important to
recognize that high amounts of sedentary time are not
synonymous with low levels of physical activity [12].
For example, an individual may achieve or exceed
physical activity recommendations but also spend long,
791
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Physical inactivity and obesity in cancer etiology C. M. Friedenreich et al.

Table 1. Summary of the observational epidemiologic evidence on the association between physical activity and cancer risk by cancer site.
Summary evidence for the dose–response effect, biologic plausibility, and overall classification of evidence was acquired from the 2018
Physical Activity Guidelines Advisory Committee [8] and McTiernan et al. [10]. Risk reduction estimates were acquired from McTiernan et al.
[10] and meta-analyses previously conducted by the authors.

Overall Approximate range of relative Evidence for

classification risk reduction for high versus dose–response Biologic
Cancer site of evidence low levels of physical activity effect plausibility

Bladder Strong 19–24% Limited Limited

Breast Strong 19–27% Yes Yes
Colon Strong 21–27% Yes Yes
Endometrial Strong 19–29% Yes Yes
Esophageal Strong 19–51% Yes Yes
adenocarcinoma
Gastric cardia Strong 15–19% Yes Yes
Renal Moderate 12–16% Limited Yes
Lung Moderate/Limiteda 27–28% Yes Limited
Ovarian Moderate 2–23% Limited Yes
Pancreas Moderate 9–25% Yes Yes
Prostate Limited 3–13% Limited Limited
a
Confounding by smoking is possible.

uninterrupted time sitting at a work computer and/or Table 2. Summary of the observational epidemiologic evidence on
watching television at home. Conversely, a person may the association between sedentary time and cancer risk by cancer
accumulate small amounts of sedentary time over a site. Summary evidence was acquired from Jochem et al. [12].
24-h period as a result of a physically demanding job,
Magnitude
but also have no or low levels of recreational physical of relative
activity. Therefore, it is important to consider both the risk
amount of time dedicated to physical activity and time increase Evidence
spent in sedentary behavior for cancer prevention. The for high for
AICR developed an educational infographic to illus- Overall versus low dose–
trate the importance of making time for physical activ- classification sedentary response Biologic
Cancer site of evidence time effect plausibility
ity and breaking up sedentary time for cancer
prevention [13]. Colon Moderate 28–44% Limited Yes
A recent update published by the 2018 PAGA Com- Endometrial Moderate 28–36% Limited Yes
mittee reported that there is moderate evidence to sug- Lung Moderatea 21–27% Limited Limited
gest that high levels of sedentary time are associated a
Confounding by smoking is possible.
with an increased risk of colon, endometrial, and lung
cancers, with limited evidence for a dose–response rela- or walking) would lead to some health benefits, with
tion [14]. Recently published reviews also corroborate the greatest benefits occurring when sedentary time is
these findings [12,15]. Specifically, high versus low replaced with planned moderate-vigorous intensity
levels of sedentary time were consistently associated physical activity [14]. Additional research from
with a range in relative risks (RR) of 1.28–1.44 for prospective cohort studies is needed to assess the inter-
colon cancer, 1.28–1.36 for endometrial cancer, and active effects of physical activity and sedentary time
1.21–1.27 for lung cancer (Table 2). on cancer incidence [14]. Randomized controlled trials
Given that a high proportion of individuals spend focused on promoting reductions in sedentary by
the majority (~ 55%) of their time awake taking part replacing it with light, moderate, and/or vigorous
in sedentary behaviors [16], interventions targeting intensity physical activity are also needed in individu-
reductions in sedentary time would contribute to als at high risk for cancer development.
reducing chronic disease risk, including cancer, at a
population-level. For individuals with habitually high
4. Obesity and cancer incidence
levels of sedentary time, it is expected that replacing
some of that time with light intensity or ambulatory Weight gain, which may eventually contribute to the
activities (e.g., breaking up sedentary time by standing development of obesity [body mass index (BMI)

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C. M. Friedenreich et al. Physical inactivity and obesity in cancer etiology

Table 3. Summary of the observational epidemiologic evidence on the association between obesity and cancer risk by cancer site.
Summary evidence was acquired from Lauby-Secretan et al. [19].

Overall Magnitude of relative risk

classification increase for BMI ≥ 25 Evidence for Biologic
Cancer site of evidence versus BMI < 25 dose–response effect plausibility

Colorectal Strong 10–30% Yes Yes

Gastric cardia Strong 20–80% Yes Yes
Esophagus Strong 15–480% Yes Yes
Liver Strong 50–80% Yes Yes
Postmenopausal breast Strong 10–12% Yes Yes
Gallbladder Strong 20–60% Yes Yes
Endometrial Strong 50–710% Yes Yes
Renal/kidney Strong 30–80% Yes Yes
Meningioma Strong/Moderate 40–213% Limited Limited
Pancreatic Strong 20–50% Yes Yes
Multiple myeloma Strong/Moderate 15–52% Limited Limited
Ovarian Moderate 10–20% Yes Yes
Thyroid Moderate 4–17% Yes Yes

≥ 30 kg
m 2], occurs when energy intake exceeds
energy requirements from resting metabolic needs
and physical activity energy expenditure. The preva-
lence of overweight (BMI ≥ 25 kg
m 2) and obesity
(BMI ≥ 30 kg
m 2) in adults aged ≥ 18 years is 39%
and 13%, respectively [17]. These stark overweight
and obesity levels constitute a main determinant of
the increasing prevalence of many cancer types that
could surpass smoking as the main preventable cause
of cancer [18]. Indeed, the International Agency for
Research on Cancer (IARC) established that there is
convincing evidence that excess body fatness (i.e.,
highest BMI category evaluated versus normal BMI
of 18.5–24.9 kg
m 2) is associated with an increased
risk of at least 13 different types of cancers (RRs
ranging from 1.1 to 7.1), including endometrial, post-
menopausal breast, colorectal, esophageal, renal/kid-
neys, meningioma, pancreatic, gastric cardia, liver,
multiple myeloma, ovarian, gallbladder, and thyroid
(Table 3) [19]. The WCRF/AICR also highlighted
that there is convincing and sufficient evidence that
obesity is associated with an increased risk of
endometrial, esophageal, colorectal, liver, pancreatic,
postmenopausal breast, and renal/kidney cancers [9].
Taken together, there is strong evidence that obesity
is associated with cancers impacting digestive organs
in men and women, as well as hormone-sensitive
organs/sites in women [20].
Given the strong association between obesity/
weight gain and cancer, it is assumed that weight
loss may be a viable prevention approach for reduc-
ing cancer risk. A systematic review that included 34
studies reported that 16 of these studies found a sta-
tistically significant reduction in cancer risk in
individuals who experienced weight loss [21]. Specifi-
cally, studies assessing the risk of cancer following
bariatric surgery reported that patients who had
received this surgery had a statistically significantly
decreased risk of combined cancers when compared
to controls with obesity (RRs ranging from 0.22 to
0.76) over a five to 12.5-year follow-up period [21].
Nonsurgical approaches to intentional weight loss
defined as ≥ 9 kg weight loss since age 18 were also
associated with a significant decrease in combined
cancer incidence (RR = 0.88) over a 7-year follow-up
period [21]. The observed benefits of weight loss on
cancer risk were strongest in women (with mostly
null findings in men) and most consistent for obesity-
related cancers [21]. Despite these findings, the
impact of sustained long-term weight loss and the
increased risk of weight regain following weight loss,
on cancer incidence, needs to be studied further to
better inform weight loss strategies for cancer preven-
tion. The avoidance of weight gain may also be a
more viable target than sustained weight loss as a
cancer preventive measure, given the several physio-
logical alterations that persist beyond the initial
weight loss period to promote weight regain [22].
These alterations include decreases in anorexigenic
hormones such as leptin, increases in orexigenic hor-
mones such as ghrelin, decreases in resting metabolic
rate that are greater than what can be accounted for
by changes in body weight (adaptive thermogenesis),
increases in appetite sensations, and lower fat oxida-
tion in the weight-reduced state [22]. Further research
is needed to provide evidence on various approaches
to weight gain prevention and weight loss strategies
for cancer prevention [20].

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Physical inactivity and obesity in cancer etiology C. M. Friedenreich et al.

biomarkers and need to be considered when evaluating

5. Biologic mechanisms linking
physical inactivity, sedentary
behavior, and obesity with cancer risk
Several hypothesized biologic mechanisms whereby
obesity, physical activity, and sedentary behavior influ-
ence cancer risk are being elucidated through a combi-
nation of observational and experimental research
studies (Fig. 1). The biologic pathways relating these
exposures to tumorigenesis are incompletely defined
and understood, but generally center on maintaining a
healthy body weight, thereby reducing the risk of
metabolic abnormalities, chronic low-grade inflamma-
tion, and overstimulation of endogenous sex hor-
mones. Evidence suggests that promoting physical
activity and reducing sedentary behaviors can lead to
cancer-preventing health benefits through the above-
mentioned mechanisms, independently of body fat.
Furthermore, the accumulation of ectopic fat tissue
(i.e., the storage of triglycerides in areas outside of adi-
pose tissue, such as the liver, skeletal muscle, the heart,
and the pancreas) is of particular concern since it can
interfere with normal cellular and organ function, thus
increasing the risk for many chronic diseases including
cancer [20,23]. Finally, individual characteristics, such
as age, sex, ethnicity/race, and genetics, as well as
additional modifiable lifestyle factors (e.g., diet and
smoking), may also modify the effects of physical
activity, obesity, and sedentary behavior on these
this evidence.
5.1. Metabolic function and insulin sensitivity
Insulin and insulin-like growth factor (IGF)-I are ana-
bolic endocrine hormones with important physiological
roles in glucose metabolism, as well as cell proliferation,
cell death, and angiogenesis. Overstimulation of these
biomarkers, their related binding proteins [i.e., insulin-
like growth factor-binding protein (IGFBP)-1 through -
6], and their signaling pathways have been associated
with increased risk of several malignancies such as
breast, prostate, and colorectal cancers, but the exact
molecular mechanisms by which this risk reduction
occurs are not completely understood [20]. It is well
established that excess body fat, particularly abdominal
fat, is positively correlated with insulin resistance. When
there are consistently high levels of blood glucose, excess
insulin is secreted from the pancreas and commonly
results in hyperinsulinemia leading to decreased
IGFBP-3 and subsequently increased levels of free IGF-
I, which may promote tumorigenesis [24]. In post-
menopausal women, there is evidence that this pathway
also modifies the bioavailability of sex hormones.
Specifically, prolonged hyperinsulinemia reduces
bioavailable sex hormone-binding globulin (SHBG) and
increases circulating estrogens and androgens, which
may further contribute to tumorigenesis [24].

↑ Metabolic funcon
Fig. 1. Hypothesized biologic
↑ Insulin sensivity, ↓ IGF-1, mechanisms linking physical
↑ Physical
↑ IGFBP-3, ↓ Fasng glucose activity, excess body fat, and
acvity
sedentary behavior to cancer risk.
IGF-1, insulin-like growth factor-1;
IGFBP-3, insulin growth factor-
↓ Chronic low-grade inflammaon binding protein-3; IL-6, interleukin-6;
TNF-a, tumor necrosis factor-a; IL-
↓ Lepn 1b, interleukin-1b; CRP, C-reactive
↓Adipokines protein; SAA, serum amyloid A;
↑ Adiponecn ↓ Cancer
↓ ↓ SHBG, sex hormone-binding
Overweight Adipose risk
↓ CRP globulin.
ssue ↓ ↓ IL-6
& obesity
Inflammatory ↓ TNF- α ↓ SAA
cytokines ↓ IL-1β

↓ ↓ Bioavailable sex hormones

Sedentary
behavior ↓ Estrogens
↑ SHBG
↓ Androgens

Strong evidence Moderate evidence

794 Molecular Oncology 15 (2021) 790–800 ª 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

C. M. Friedenreich et al.
Modifiable lifestyle factors such as caloric restriction
and physical activity are effective interventions for
reducing adipose tissue and correcting metabolic
abnormalities, thereby lowering the risk of certain can-
cers. Independently, and through its effect on adipose
tissue, physical activity has been shown in observa-
tional epidemiologic studies and randomized con-
trolled trials (RCTs) to reduce plasma insulin and
increase insulin sensitivity and glucose metabolism
[25]. Observational studies have also supported the
hypothesis that physical activity lowers IGF-1 levels
and raises IGFBP-3 levels [25]. However, findings from
RCTs have failed to replicate these results, concluding
that despite large reductions in weight and/or
increased levels of physical activity, IGF-1 bioavail-
ability may not facilitate the relationship between obe-
sity and cancer risk [26]. Finally, evidence is emerging
that interventions targeting sedentary behavior, with
or without physical activity, have small but statistically
significant effects on insulin levels in adults [27].
5.2. Chronic low-grade inflammation
Adipose tissue is a metabolic organ primarily com-
posed of adipocytes that secrete an array of bioactive
signaling molecules including pro-inflammatory
adipokines and cytokines that may stimulate cancer
development. Leptin is an adipocyte-derived hormone
that informs the hypothalamus about the metabolic
status of the body such that is suppresses appetite and
increases energy expenditure when fat mass accumu-
lates. However, consistently high levels of circulating
leptin may contribute to ‘hyperleptinemia’ or leptin
resistance in individuals with obesity, thus reducing
the hypothalamus’ response to leptin and current
energy stores. In addition to reducing its impact on
appetite and energy expenditure, this state of leptin
resistance also perpetuates inflammation [28]. In con-
trast, adiponectin is an apoptosis-inducing adipokine
that is released by the adipocytes, but acts as an insu-
lin-sensitizing hormone by increasing glucose uptake
and reducing triglyceride uptake in the muscle, and
suppressing glucose production and triglyceride storage
in the liver [28]. Adiponectin production is, however,
reduced in individuals with obesity in response to
increased production of pro-inflammatory cytokines
[e.g., tumor necrosis factor-alpha (TNF-a)], contribut-
ing to a state of ‘hypoadiponectinemia’ and increased
tumorigenesis [28]. Finally, pro-inflammatory cytokines
themselves, including interleukin-6 (IL-6), IL-1b, and
TNF-a, released by adipocytes increase the production
of C-reactive protein (CRP) and serum amyloid A
(SAA) and may contribute to tumorigenesis [28,29].
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Physical inactivity and obesity in cancer etiology
Generally, regular physical activity is thought to
have anti-inflammatory effects. Clinical studies have
demonstrated that longer-term physical activity inter-
ventions successfully reduce systemic levels of pro-in-
flammatory biomarkers and increase levels of anti-
inflammatory biomarkers at least, in part, by
decreasing adiposity [30]. There is a dearth of RCTs
examining the inflammatory effects of sedentary
behavior. Observational studies suggest that sitting
time positively correlates with higher levels of
adipokines and their related biomarkers, but these
relationships are also likely mediated by adiposity
levels [31].
5.3. Sex hormones
SHBG regulates the bioavailability of free estrogens,
which if unbound, are considered to be highly active
and associated with increased risk of some hormone-
sensitive cancers, particularly breast cancer. Observa-
tional studies and RCTs of women at risk of breast
cancer have determined that higher levels of physical
activity result in statistically significant reductions in
estradiol, free estradiol, and estrone, while increasing
levels of SHBG, regardless of menopausal status [30].
However, the evidence is stronger for postmenopausal
than premenopausal women [30]. Furthermore, there is
growing support for the hypothesis that body fat loss
is mainly responsible for mediating the effect of physi-
cal activity on sex hormones [30,32]. Evidence from
studies of cancer-free women suggests that interven-
tions combining caloric restriction with physical activ-
ity are most effective to produce favorable changes in
endogenous sex hormones [33].
Androgens, produced primarily in men and to a les-
ser extent in women, have also been implicated in
tumorigenesis. In the male prostate, androgen and
androgen receptors regulate the rate of cell growth
and death, and are closely involved with the develop-
ment of prostate cancer [34]. However, epidemiologic
studies of the relationship between androgen levels and
prostate cancer risk have been inconsistent [35]. There
is also evidence that the androgen-signaling pathway
influences breast carcinogenesis, but the direction of
effect differs among clinical and observational research
[36]. Physical activity and obesity have both been
investigated as factors that may affect androgen levels
in men and women. In men, there appears to be a
strong negative correlation between adiposity and free,
bioavailable, and total testosterone, but the relation-
ship with physical activity remains inconclusive [25]. In
women, obesity corresponds with excess levels of
androgens and physical activity is associated with
795

Physical inactivity and obesity in cancer etiology
small, but statistically significant reductions in free
testosterone and other androgens [32,37].
5.4. Emerging hypotheses
There are a number of additional biologic mechanisms
related to physical activity, obesity and sedentary
behavior under active investigation for their role in
cancer development. The biologic relevance of these
pathways for cancer has been supported by experimen-
tal findings, yet they lack, or are inconsistent with, the
epidemiologic evidence required to support them more
convincingly. Discrepancies may be the result of ran-
dom error or systematic biases arising from the use of
self-report measures of physical activity or sedentary
behavior, and the challenges inherent in laboratory
analyses of some of these other pathways [15].
Physical activity is hypothesized to affect the bal-
ance between reactive oxygen species (ROS) and
antioxidant defenses that can result in oxidative stress
[30]. ROS may cause chromosomal abnormalities,
DNA damage, and mutations in tumor-suppressing
genes. Acute exercise appears to promote oxidative
stress and a pro-oxidant environment but as physical
activity is repeated, adaptations to this stress occur
and eventually antioxidant defenses are built up
[30,38]. Correspondingly, individuals with obesity exhi-
bit lower levels of antioxidants and higher levels of
oxidative stress, which may also decrease insulin sensi-
tivity and lead to insulin resistance [39].
A similar pattern emerges from the relationship
between physical activity and immune function,
whereby the body responds differently to acute and
prolonged bouts of exertion [40]. Bouts of unusually
heavy and/or long exertions (e.g., running a marathon)
can lead to transient immune dysfunction, while
shorter duration aerobic physical activity stimulates
short-term increases in immunoglobulins, neutrophils,
natural killer cells, cytotoxic T cells, and immature B
cells, which over time, enhance immunosurveillance
[40]. These findings are particularly relevant to individ-
uals with impaired immunity, including older adults
and individuals with obesity [25].
Physical activity may affect the development of can-
cer through epigenetic alterations to chromosomes,
DNA methylation, expression of microRNA, and
chromatic structure [25]. Telomere length, a prognostic
marker of aging and disease, has been shown to be
longer in men with healthy eating and exercise habits
[25]. Part of this association may be explained by dam-
age caused to telomere length by ROS [41]. Altered
patterns of DNA methylation, considered to be a hall-
mark of cancer for its regulation of tumor suppressor
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C. M. Friedenreich et al.
genes and oncogenes, continues to be studied as a pos-
sible link between obesity and cancer risk [42,43]. In
observational studies, higher self-reported physical
activity was associated with a favorable increase in a
surrogate marker of global DNA methylation [41].
Thus far, the association between global DNA methy-
lation and obesity is inconsistent.
Emerging evidence suggests that an altered intestinal
microbiome may explain some of the association
between obesity and cancer, as microbiota may pro-
duce cancer-promoting metabolites, or promote
inflammation and insulin resistance [20]. Obesity-re-
lated inflammation originates in the intestinal lumen,
where bacteria-derived substances leak into the blood-
stream and are thought to initiate inflammation [20].
Toxic metabolites produced in response to obesity and
a high fat diet appear to cause DNA damage through
the formation of ROS. In support of this hypothesized
pathway, recent systematic reviews of observational
studies in humans have demonstrated that individuals
with obesity have a different microbial profile than
lean individuals and that microbial dysbiosis (or ‘im-
balance’) is associated with colorectal cancer [44,45].
6. Recommendations for future
epidemiologic research directions
Significant knowledge gaps remain in our understand-
ing of the biologic pathways that link physical inactiv-
ity, sedentary behavior, and obesity with increased
cancer risk. These gaps highlight potential directions
of future research (Table 4). Additional systematic
reviews and meta-analyses are needed to pool and
strengthen the evidence for cancer sites for which the
evidence is currently limited or emerging (Tables 1–3).
In addition to emerging evidence on the link between
physical activity, sedentary behavior, and obesity with
several types of cancer, accumulating evidence shows
that race/ethnicity, age, and socioeconomic status,
among other demographic characteristics, can have
profound impacts on these risk factors for cancer inci-
dence and the biologic pathways involved [46]. Despite
this evidence, the majority of studies do not assess
effect modification by these key demographic charac-
teristics, while including a large number of participants
who have high socioeconomic status, education, and/
or are White. Therefore, findings may lack generaliz-
ability to more diverse and minority populations [46]
who may gain the most benefit from lifestyle modifica-
tions on reducing cancer risk. Addressing barriers to
participation in clinical trials for minority populations
(i.e., mistrust, experimentation fears, low socioeco-
nomic status, logistical barriers) could serve to
 18780261, 2021, 3, Downloaded from https://febs.onlinelibrary.wiley.com/doi/10.1002/1878-0261.12772 by Cochrane Chile, Wiley Online Library on [07/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
C. M. Friedenreich et al. Physical inactivity and obesity in cancer etiology

Table 4. An outline of recommendations for future research directions.

Exposure type (physical activity,

sedentary behavior, obesity, or all) Recommendations for future research directions/studies

All Study effect modification by age, race/ethnicity, socioeconomic status

All Conduct pooled analyses, meta-analyses and large prospective cohort studies for cancer sites with
limited or unassignable grades of evidence
Physical activity and sedentary Include both self-report and device-based measures of physical activity and sedentary time to
time improve quantification of these behaviors
Physical activity and sedentary Examine the dose–response associations between physical activity and sedentary time with cancer
time risk
Physical activity Assess the association between different parameters of activity (frequency, intensity, type,
duration, and volume) on cancer incidence
Physical activity Assess the effects of different exercise prescriptions varying in intensity, type, duration, volume,
and progression on biomarkers for cancer incidence
Sedentary time Examine the association between sedentary time and cancer risk for cancer sites for which the
evidence is currently limited or unavailable
Sedentary time Assess effects of reducing sedentary time on biologic markers of cancer risk
Sedentary time Assess role of standing and breaking up sedentary time on cancer risk
Obesity Use direct quantification of excess body fat and body fat distribution (e.g., waist and hip
circumferences, visceral and subcutaneous abdominal fat mass, total fat mass)
Obesity Assess body weight change and weight loss in behavioral interventions (diet and/or physical activity
interventions)
Obesity Assess how weight gain and/or weight loss influence biomarkers for cancer risk

improve health outcomes and reduce public and pri-
vate medical expenditures in these populations [47].
Moreover, future studies should use both self-report
and device-based (e.g., accelerometry) measurement
tools to improve the quantification of physical activity
and sedentary behaviors, as well as provide context to
these behaviors. Additionally, studies are needed to
provide evidence on the associations between charac-
teristics of physical activity (frequency, intensity, type,
duration, and volume) and sedentary time (standing
time and breaks in sedentary behaviors) with cancer
incidence and intermediate biomarkers for cancer risk.
These results could then be used to inform the design
and conduct of RCTs targeting changes in one or
more of these physical activity and/or sedentary behav-
ior characteristics. For example, the Breast Cancer and
Exercise Trial in Alberta (BETA) aimed to assess the
effects of different exercise durations on biomarkers
for postmenopausal breast cancer risk in 400 post-
menopausal, previously inactive women. These women
were randomized to either 150 or 300 min per week of
aerobic exercise for 1 year [48]. The study concluded
that higher doses of physical activity are superior to
the recommended dose for reducing adiposity, but not
for improving other biomarkers of insulin resistance,
inflammation, or endogenous sex hormones [48,49].
Additional RCTs, similar to BETA, that focus on
comparing other components of an exercise prescrip-
tion, as well interventions that focus on reducing
sedentary time or on biomarkers for cancer risk would
add to this literature.
Lastly, more studies are needed to improve under-
standing of the etiologic role of excess body fat, rather
than body weight, on cancer risk by including mea-
sures other than BMI, such as waist and hip circum-
ferences, visceral and subcutaneous fat mass, and total
fat mass. Furthermore, prospective cohort studies that
focus on the role of body weight change and weight
loss in cancer prevention, in addition to RCTs that
assess the impact of behavioral interventions (diet and/
or physical activity interventions) targeting weight loss
on biomarkers for cancer risk, are needed. Observa-
tional studies and RCTs could also assess the impact
of the rate of weight gain and/or weight loss on
biomarkers for cancer incidence, as these results could
be used to inform the ‘intensity’ of behavioral pre-
scriptions needed to induce weight loss or prevent
weight gain for cancer prevention.
7. Conclusion
In this review, we summarized the epidemiologic evidence
relating physical activity, obesity, and sedentary behavior
with cancer incidence and described established and
emerging pathways that support the biologic plausibility
of these relationships. Currently, there is strong evidence
that physical inactivity and obesity independently
increase the risk of multiple cancers, and some evidence

Molecular Oncology 15 (2021) 790–800 ª 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd. 797

Physical inactivity and obesity in cancer etiology
that sedentary behavior has a similar effect. Additional
research is needed to increase the depth and scope of
knowledge pertaining to these associations.
Globally, high rates of physical inactivity, excess
body fat, and sedentary time contribute substantially
to the development of noncommunicable diseases
including cancer. High BMI, in particular, is a risk
factor that continues to increase in prevalence, even in
developing countries [50]. Changes to the food envi-
ronment, including the marketing and availability of
energy-dense foods, and increasing wealth may be pri-
mary drivers of this trend [50]. Increases in urbaniza-
tion, sedentary jobs, and leisure-time spent at the
computer or watching television have further led to
inactive lifestyles and increase the risk of multiple non-
communicable diseases [50]. Through translation and
dissemination of research, public health organizations
and primary healthcare providers can increase aware-
ness and promote healthy behaviors that reduce the
overall burden of cancer.
Conflict of interest
The authors declare no conflict of interest.
Author contributions
CMF, CR-B, and JM contributed equally to the con-
ceptualization and writing of this review.
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